Medicinal product and method for treatment of conditions affecting neural stem cells or progenitor cells

ABSTRACT

Use of a substance that upon administration will lead to increased concentrations of growth hormone, such as growth hormone, a functionally equivalent analogue thereof or a substance that will increase the release of endogenous growth hormone, for the production of a medicinal product for treatment of abnormal conditions affecting neural stem cells, progenitor cells and/or cells derived from neural stem cells or progenitor cells, especially conditions affecting the oligodendroglia, astroglia, and/or neuronal cells. In vitro and in vivo methods for inducing lineage determination, propagating and/or inducing or maintaining the genesis of neurons, oligodendrocytes, astroglial cells from progenitor cells, stem cells and/or cells derived from said cells by administrating to the cells a substance that increases the concentration of growth hormone. Also a method of reducing the genesis of oligodendrocytes, neurons, astroglial cells from progenitor cells or stem cells, wherein a pharmaceutically effective amount of a substance that will lead to a decreased concentration of growth hormone or a functionally equivalent analogue thereof is administered to said patient.

FIELD OF INVENTION

The present invention relates to use of substances that uponadministration to a patient will lead to increased concentrations ofgrowth hormone for the production of medicinal products.

The present invention also relates to a method for treatment of abnormalconditions affecting neural stem cells or progenitor cells.

BACKGROUND OF THE INVENTION

The result of traumatic, asfyxial, hypoxic, ischemic, toxic, infectious,degenerative or metabolic insults to the central nervous system (CNS) ofman may involve a certain degree of damage in several different celltypes. Damage to the brain by trauma, asphyxia, toxins, ischemia orinfections are frequently causing neurological and cognitive deficits.Degenerative diseases may cause loss of specific populations of cells.For instance Parkinson's disease is associated by specific loss ofdopaminergic neurons in the Substantia nigra, similarly, multiplesclerosis is associated with loss of myelin and oligodendrocytes. Otherexamples of degenerative disorders caused by selective loss of aspecialized type of neurons is Alzheimer's disease associated with lossof cholinergic neurons. There are many other instances in which CNSinjury or disease can cause damage to oligodendroglia, astroglia orneuronal cells.

Furthermore, axonal regeneration and sprouting after injury to axons inthe CNS white mater tracts and injury to the spinal cord has been shownto be inhibited by surface molecules expressed by oligodendrocytes.

Progenitor cells have been grown and propagated with growth factors likeepidermal growth factor (EGF), which is a substance belonging to adifferent class than GH.

In general, replacement of neurons following degeneration or damage isnot a characteristic of the mammalian brain. Neuronal loss is thusconsidered permanent. Prolonged postnatal neurogenesis has beendescribed in the granule cell layer of the hippocampal formation(Altman, J., and Das, G. D., J. Comp. Neurol. 124: 319-335 (1965);Altman, J. and Das, G. D. Nature 214: 1098-1101 (1967); Caviness, V. S.jr., J. Comp Neurol. 151: 113-120 (1973); Gueneau, G., Privat, A.,Drouet, J., and Court, L., Dev. Neurosci. 5, 345-358(1982); Eckenhoff,M. F., and Rakic, P., J. Neurosci. 8: 2729-2747(1988)). Neurogenesis hasrecently been shown to persist well into adulthood in man (Eriksson, P.S., Perfilieva, E., Björk-Eriksson, T., Alborn, A., Nordborg, C.,Peterson, D. A., Gage, F. H., Nature Med. in press). Neuronal progenitorcells reside in the subgranular zone (SGZ) of the dentate gyrus wherethey continuously proliferate, migrate into the granulae cell layer anddifferentiate into granule cells (Kuhn, H., Dickinson-Anson, H., andGage, F. H., J. Neurosci. 16: 2027-2033 (1996); Cameron, H. A., Woolley,C. S., McEwen, B. S., and Gould, E., Neuroscience 56: 337-344 (1993);Seki, T. and Arai, Y., J. Neurosci. 13: 2351-2358 (1993)). These newbornneurons in the granule cell layer express markers of differentiatedneurons and have morphological characteristics corresponding todifferentiated granulae cells (Kaplan, M. S. and Bell, D. H., J.Neurosci. 4: 1429-1441 (1984); Cameron, H. A., Woolley, C. S., McEwen,B. S. and Gould, E. Neuroscience 56: 337-344 (1993); Cameron, H. A.,Woolley, C. S., and Gould, E., Brain Res. 611: 342-346 (1993)).Furthermore, they establish axonal processes into the mossy fiberpathway and form synaptic connections with their targets in hippocampusCA3 (Seki, T. and Arai, Y., J. Neurosci. 13: 2351-2358 (1993);Stanfield, B. B. and Trice, J. E. Exp. Brain Res. 72: 399-406 (1988)).The hippocampus is associated with spatial learning and memory(McNamara, R. K, and Skelton, R. W., Brain Res. Rev. 18: 33-49 (1993)).The proliferation of progenitor cells can be influenced by theadministration of n-methyl-d-aspartate (NMDA) receptor antagonists or bythe removal of the adrenal glands (Cameron, H. A. and Gould, E.Neuroscience 61: 203-209 (1994); Cameron, H. A., Tanapat, P., and Gould,E., Neuroscience 82: 349-354 (1998)). Plasticity is reduced withincreasing age, and recent studies have demonstrated that proliferationof progenitor cells also is decreased but not completely abolished withage (Kuhn, H., Dickinson-Anson, H., and Gage, F. H., J. Neurosci. 16:2027-2033 (1996)). Stem cells isolated from the adult rodent brain hasrecently been transplanted into the brain of adult animals where theydifferentiate into cells with neuronal characteristics (Suhonen, J. O.,Peterson, D. A., Ray, J. And Gage, F. H., Nature 383: 624-627 (1996)).

Furthermore, neurogenesis in the dentate gyrus in young mice has beenshown to be facilitated by enriched environments. It was shown thatexposure to enriched environments leads to an increased number ofsurviving newly formed granulae cell neurons and an increased totalnumber of neurons in the dentate gyrus (Kempermann, G., Kuhn, H. G., andGage, F. H., Nature 386: 493-495 (1997)).

SUMMARY OF THE INVENTION

It has now been found that by using growth hormone, or an analoguethereof, or another substance leading to increased concentrations ofgrowth hormone or analogues thereof, it is possible to modulate theproliferation and/or differentiation of neural stem cells and progenitorcells from the adult CNS. The present invention thus provides newpossibilities to treat injuries to or diseases of the central nervoussystem that predominantly affect oligodendroglia, astroglia or neuronalcells by modification of proliferation cell genesis and/ordifferentiation of neuronal stem cells or progenitor cells in thecentral nervous system.

It has also been found that it is possible to control the propagation invitro of stem cells, progenitor-cells and other cells, especially cellsderived from the central nervous system, with the potential to generateneurons, astrocytes or oligodendrocytes. Such cells may e.g. be used fortherapeutic purposes in patients.

Thus, the present invention relates to the use of a substance that-uponadministration to a patient will lead to an increased concentration ofgrowth hormone or a functionally equivalent analogue thereof for theproduction of a medicinal product for treatment of an abnormal conditionaffecting neural stem cells and/or progenitor cells.

The invention also relates to a method for treatment of an abnormalcondition affecting neural stem cells and/or progenitor cells, wherein apharmaceutically active amount of a substance that will lead to anincreased concentration of growth hormone or a functionally equivalentanalogue thereof is administered to a patient.

Furthermore, the invention relates to a method of inducing lineagedetermination, propagating and/or inducing or maintaining the genesis ofneurons, oligodendrocytes, astroglial cells from progenitor cells, stemcells and/or cells derived from said cells by administration of aneffective amount of growth hormone or a functionally equivalent analoguethereof to stem cells, progenitor cells, neurons astroglial cells and/oroligodendrocytes in vitro.

Another aspect of the invention relates to abnormal conditions in theCNS due to too high concentrations of growth hormone in the CNS.

The invention thus also relates to the use of a substance that uponadministration to a patient will lead to a decreased concentration ofgrowth hormone or a functionally equivalent analogue thereof for theproduction of a medicinal product for treatment of an abnormal conditionaffecting stem cells, progenitor cells and/or cells derived from stemcells or progenitor cells; as well as to a method of reducing thegenesis of oligodendrocytes, neurons, astroglial cells from progenitorcells or stem cells in, or derived from, the central or periferalnervous system in a patient, wherein a pharmaceutically effective amountof a substance that will lead to a decreased concentration of growthhormone or a functionally equivalent analogue thereof is administered tosaid patient.

The characterizing features of the invention will be evident from thefollowing description and the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The mammalian brain, including the human brain, retains its ability togenerate neurons throughout life in certain brain regions. New neuronsand astroglial cells and oligodendrocytes are generated by cell genesisfrom stem or progenitor cells. During the research leading to thepresent invention it was found that growth hormone (below denoted GH)induces an increase in cell genesis from progenitors/stem cells in theadult brain. It was also found that increased number of new cells in thehippocampus is associated with improvement in learning and memory. Thesefindings lead to the insight that it is possible to manipulateneurological deficits, such as memory and learning deficits, in patientsby manipulating the amount of GH present in the environment surroundingthe cells.

It was thus found that it is possible to treat a CNS damage or deficitafter an insult by increasing the number of stem cells or progenitorderived cells including neurons, astroglial cells and oligodendrocytes.

It was also found that it is possible to treat neural loss sufferedafter a CNS insult by increasing the number of stem cells or progenitorderived cells including neurons, astroglial cells and oligodendrocytesin a patient by increasing the concentration of GH in the patient toinduce proliferation and/or differentiation of stem cells-with aconcomitant increase in cell genesis.

Finally it was found that it is possible to treat neural loss sufferedafter a CNS insult by increasing the number of stem cells or progenitorderived cells including neurons and/or astroglial cells and/oroligodendrocytes in a patient by increasing the concentration of GH inthe patient to induce proliferation and/or differentiation of stem cellswith a concomitant increase in cell genesis in order to facilitate theisolation through surgical removal of small samples of brain tissuecontaining said cells for further expansion in vitro and concomitantre-transplantation into the patient.

Thus, the present invention relates to the use of a substance that uponadministration to a patient will lead to an increased concentration ofgrowth hormone, or of an analogue thereof, for the production of amedicinal product for treatment of an abnormal condition affectingneural stem cells, progenitor cells and/or cells derived from neuralstem cells or progenitor cells, as well as to a method for treatment ofan abnormal condition affecting neural stem cells, progenitor cellsand/or cells derived from neural stem cells or progenitor cells, whereina pharmaceutically active amount of a substance that will lead to anincreased concentration of growth hormone is administered to a patient.

The substance that will lead to an increased concentration of growthhormone or analogue thereof may e.g. be growth hormone itself, or afunctionally equivalent analogue thereof. The term “functionallyequivalent analogue thereof” relates to all substances that uponadministration to a patient will have essentially the same biologicaland pharmaceutical effect as GH. Such an analogue may e.g. be asynthetic GH mimetic. It is also possible to use a compound that uponadministration to a patient will give rise to an elevated activeconcentration of GH or of a natural occurring GH analogue or itsmediators in the CNS of the patient, e.g. by giving rise to an increasedrelease of endogenous GH. For example, positively regulating bindingproteins of GH may be used, such as the GH releasing substance growthhormone releasing peptide (GHRP) and analogous thereof.

The medicinal product according to the invention preferably comprisesthe active substance in a pharmacologically acceptable carrier ordiluent such as those known in the art.

The medicinal product or the substance used according to the inventionis preferably administered via intravenous periferal infusion or viaintramuscular or subcutaneous injection into the patient. It is alsopossible to administer the medicinal product or the pharmaceuticallyactive substance through a surgically inserted shunt into a cerebralventricle of the patient.

Preferably, the administered subcutaneous dosage range of thepharmaceutically active substance is about 0.01-1 IE/kg body weight ofthe patient per week.

The term “patient”, as used herein, relates to any human or non-humanmammal in need of treatment according to the invention.

The term “treatment” used herein relates to both treatment in order tocure or alleviate a disease or a condition, and to treatment in order toprevent the development of a disease or a condition. The term treatmentalso refer to the affecting of cell genesis from stem cells orprogenitor cells, by inducing the genesis of neurons and/or glial cellsafter either neuronal, oligodendroglial or glial cell loss in the CNS orPNS (periferal nervous system) or to prevent the normal age relateddeterioration in the CNS or PNS, the term also relates to thecultivation of stem or progenitor cells for concomitant transplantationto the CNS or PNS in patients. The treatment may either be performed inan acute or in a chronic way.

As stated above the pharmaceutically active substance used according tothe invention is suitable for treatment of abnormal conditions affectingneural stem cells, progenitor cells and/or cells derived from neuralstem cells or progenitor cells. It can thus be used to prevent, treat orameliorate damages, diseases or deficits of central nervous system(CNS). The pharmaceutically active substance used according to theinvention is especially suitable for treatment of conditions affectingthe oligodendroglia, astroglia, and/or neuronal cells. Such conditionsmay e.g. be a CNS damage or deficit, neuronal cell loss or memory loss.Such conditions may be caused by a number of different factors ordiseases, such as multiple sclerosis, hypoxic injury, ischemic injury,traumatic injury, Parkinson's disease, and demyelition disorder.

The effect the pharmaceutically active substances used according to theinvention is due to their ability to either induce cell genesis,proliferation and/or differentiation of progenitor derived cells in orfrom the central nervous system.

According to another embodiment of the invention it is possible to usegrowth hormone or a functionally equivalent analogue thereof in order topropagate progenitor cells or stem cells or other neural cells in atissue culture or a cell culture. Such cells may thereafter be used forcell transplantation into a patient suffering from neuronal cell loss ora condition due to lack of endogenous cells of this type. The cells usedto start the culture may either originate from the patient itself offrom human or animal donors.

When cells are to be removed from a patient for in vitro propagation itmay be advantageous to first increase the number of progenitor cells inthe patient. This facilitating the subsequent isolation of said cellsfrom patients facilitates the subsequent isolation of said cells frompatients. The number of progenitor cells are increased by use of themethod or medicinal product according to the invention, i.e. by the useof substance that upon administration to a patient will lead to anincreased concentration of growth hormone or a functionally equivalentanalogue thereof.

Growth hormone, or a functionally equivalent analogue thereof, may beused alone or in junction with other medicaments or growth factors suchas epidermal growth factor (EGF) or fibroblast growth factor 2 (FGF2)designed to induce in cell genesis or proliferation in the CNS or PNS.Growth hormone, or a functionally equivalent analogue thereof, alone orin conjunction with other medicaments, peptides, growthfactors,steroids, lipids, glycosylated proteins or peptides, either simultaneousor in sequence, may be used in order to facilitate cell genesis or thegeneration of specific cell types in vivo or in vitro. It may also beused to induce immature, or multipotent cells to active specificdevelopmental programs as well as specific genes in the aforementionedcells.

By the above mentioned cell genesis is meant the generation of new cellssuch as neurons oligodendrocytes schwancells and astroglial cells frommultipotent cells, progenitor or stem cells within the adult CNS or PNSor in vitro.

Furthermore, the invention also relates to the therapeutic use ofsubstances that decrease the amount of active GH or naturally occurringanalogous of GH in the patient and thus decrease the genesis ofoligodendrocytes in patients with axonal or spinal cord injury. Examplesof such substances are negatively regulating binding proteins,GH-receptor antagonists, drugs or antibodies or compounds or peptides.Axonal regeneration and spinal cord injury have been shown to beinhibited by certain molecules expressed by oligodendrocytes.Furthermore, drugs or antibodies or compounds or peptides, that increaseendogenous peptides, or proteins that decrease the biological activityof endogenous GH can also be used.

The invention will be more fully understood when reading the followingexample. It should not, however, be considered to limit the scope of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

In the examples below, reference is made to the appended drawings onwhich:

FIG. 1 shows the density of BrdU-positive cells after 7 days in thedentate gyrus of hypophysectomized (Hx) rats treated according to theinvention with growth hormone (GH), together with cortisol (C), andL-thyroxine (T) compared to hypophysectomized rats treated with only Cand T, and to a control group.

FIG. 2 shows that animals treated with cortisone, thyroxine and GH,according to the invention, had significantly more granulae cell neuronsthan hypophysectomized animals treated with only cortisone and thyroxinefour weeks after the last BrdU injection the hypophysectomized animals

FIG. 3 shows that animals with increased number of new born cellsaccording to the invention (◯) performed significantly better in thehidden-platform version of the water maze task, used to assess spatialperformance, than a control group (●).

EXAMPLES

In this example, the density of BrdU-positive cells in the dentate gyrusof hypophysectomized (Hx) rats treated according to the invention withgrowth hormone (GH), cortisol (C), and L-thyroxine (T) was compared tothe density of BrdU-positive cells in the dentate gyrus ofhypophysectomized rats treated with cortisol (C), and L-thyroxine (T),and to the density of the same cells for an untreated unoperated controlgroup.

Fisher rats (Harlan Sprague Dawley) which were intact orhypophysectomized at 50 days of age were maintained under standardizedconditions of temperature (24-26° C.), humidity (50-60%) and with lightson between 0500 and 1900 h.

The rats had free access to standard laboratory chow and water. Hormonaltreatment started 7-10 days after hypophysectomy. All thehypophysectomized rats were given cortisol phosphate (400 μg/kg/day;Solu-Cortef, Upjohn, Puurs, Belgium) and L-thyroxine (10 μg/kg/day;Sigma, USA) diluted in saline as a daily subcutaneous injection (at 0800h). Recombinant bovine GH (bGH) was diluted in 0.05 M phosphate buffer,pH 8.6, with 1.6% glycerol and 0.02% sodium azide. GH 1 mg/kg/day wasgiven as one daily subcutaneous injection at 24 h intervals. Thetreatment continued for seven days. Thereafter the rats were sacrificedand the brains taken out and prepared for immunohistochemistry.

Ten hypophysectomized rats were substituted with only cortisole andL-thyroxine. Fifteen hypophysectomized rats were substituted withcortisole, L-thyroxine and GH. Ten rats weighing 120 g were assigned toa control group. During the seven days of the treatment period allanimals received a daily intraperitoneal injection (50 mg/kg bodyweight)of bromodeoxyuridine (BrdU; Sigma). The thymidine analog BrdU isincorporated into the genetic material upon mitotic division whereafterit can be detected immunohistochemically in the resulting cells. On thetwentieth day all animals were sacrificed by a lethal dose ofanesthetics and transcardially perfused with 4% paraformaldehyde. Thebrains were removed and postfixed in 4% paraformaldehyde for 24 h. andthereafter stored in 30% sucrose solution. Coronal freezing microtomesections (40 μm) were stored in cryoprotectant (25% ethylene glycol, 25%glycerin, 0.05 M phosphate buffer) at −20° C. until processing forimmunohistochemistry or immunofluorescence.

The number of BrdU positive cells in the dentate gyrus of thehippocampus were counted using unbiased counting techniques. Fordetection of BrdU-labeled nuclei in tissue sections, the following DNAdenaturation steps preceded the incubation with mouse anti-BrdU antibody1:400 (Boeringer Mannheim): 2 h incubation in 50% formamide/2×SSC (0.3 MNaCl, 0.03 M sodium citrate) at 65° C., 5 min. Rinse in 2×SSC, 30 minincubation in 2N HCl at 37° C., and 10 min. Rinse in 0.1M boric acid, pH8,5. All stainings were performed on free floating 40 mm sections.Free-floating sections were treated with 0.6% H₂O₂ in tris bufferedsaline (TBS) (0.15M NaCl, 0.1M Tris—HCl, pH 7.5) for 30 min to blockendogenous peroxidase. Several rinses in TBS were then followed byincubation in TBS/0.25% Triton X-100/3% normal horse serum (TBS-TS) for30 min and incubation with primary antibody in TBS-TS overnight at 4° C.After rinsing in TBS-TS, the sections were incubated for 3 hr withbiotinylated horse anti-mouse IgG, 1:160 secondary antibodies (VectorLaboratories, USA). After TBS rinsing avidin-biotin-peroxidase complexwas applied for 1 h followed by peroxidase detection for 5 minutes (0.25mg/ml diaminobenzidine, 0.01% H₂O₂, 0.04% NiCl).

For the immunofluorescence, sections were treated for DNA denaturationas described above, followed by incubation in TBS-TS for 30 min.Thereafter the sections were incubated with mouse-anti-Calbindin-D28k,1:2000 (Sigma) for 16 h at 4° C. and was detected with a Texas redconjugated donkey anti-mouse IgG. BrdU was detected with a FITCconjugated rabbit anti-BrdU antibody. Fluorescent signals were detectedand processed using a confocal scanning laser microscope (Bio-RadMRC1024, Richmond, Calif.).

The total number of BrdU positive cells in the granule cell layer, thesubgranular layer and the hilus and their corresponding sample volumeswere determined in 7-9 coronal sections, 240 mm apart, that containedthe dentate gyrus. Cell counting was done according to an opticaldissector method to avoid over sampling errors.

The results are shown in FIG. 1. After 7 days, the number of newborncells in the dentate gyrus is significantly increased inhypophysectomized animals substituted with GH, cortisone, and thyroxinecompared to animals substituted with only cortisone and thyroxine.Furthermore, the rate of proliferation was significantly increased afteradministration of GH to hypophysectomized animals treated with cortisoland L-thyroxine as quantified after one week of substitution. Theseresults clearly show that GH increase the proliferative rate ofprogenitor cells in the dentate gyrus in the hippocampus.

Furthermore, the rate of proliferation was significantly increased afteradministration of GH to hypophysectomized animals treated with cortisoland L-thyroxine as quantified after one week of substitution. Thisresult suggest that GH affect the proliferative rate of progenitor cellsin the dentate gyrus of the hippocampus.

Furthermore, the proliferation was increased in normal animals receivingtreatment for one week with GH compared with normal controls andcompared with the hypophysectomized animals that were substituted forone week and thereafter unsubstituted during the following 3 weeks. Thenumber of BrdU positive cells were estimated one month after treatmentwith either cortisone and L-thyroxine or cortisone, L-thyroxine and GH.The results are shown in FIG. 2.

The results suggest that GH either direct or indirect promoteproliferation or survival of cells resulting from neural cell progenitorproliferation in the dentate gyrus.

The inventors of the present invention are the first to show that growthhormone can regulate the proliferation and subsequent generation ofneurons in the adult brain.

Rats with increased number of newborn cells were tested and comparedwith rats that had lower number of newborn cells four weeks after BrdUinjection during four consecutive days. The rats were tested in a watermaze with a video-tracking system. The time to reach the platform(latency) were monitored. The escape platform was hidden 1 cm below thesurface of the water at a fixed position. The water was made opaque byadding dry milk powder to the water. The water temperature was keptconstant at 22° C. throughout the test. Each animal was tested in fourtrials each day. Each trial lasted 45 s. Animals that failed to find thehidden platform within 45 s were designated as having a 45-s latency andwere put on the platform and allowed to stay there for 15 s.

The latency in finding the platform during the water maze test wasanalyzed with a two-way ANOVA, and repeated postcomparative tests ateach monitored time interval were performed using the Scheffe F-test.The results are shown in FIG. 3. There were no significant difference inswim speed. It is evident that animals with increased number of newborncells in the dentate gyrus, due to treatment according to the invention,performed significantly better in the spatial learning task. These groupof animals represent the data denoted with ◯ in the figure. The data forthe rats with the lower number of newborn cells are denoted with ● inthe figure.

1-31. (Canceled)
 32. A method for the treatment of CNS damage affectingneural stem cells, progenitor cells and/or cells derived from stem cellsor progenitor cells comprising administering an effective amount ofgrowth hormone or a functionally equivalent analog thereof to a patientin need of such treatment.
 33. The method according to claim 32, whereinsaid CNS damage affects the oligodendroglia, astroglia, and/or neuronalcells.
 34. The method according to claim 32, wherein said CNS damageaffects non-cholinergic neuronal cells, cholinergic neuronal cells, orglial cells.
 35. The method according to claim 32, wherein said CNSdamage is neural cell loss.
 36. The method according to claim 32,wherein said CNS damage is caused by hypoxic injury, ischemic injury, ortraumatic injury.
 37. The method according to claim 32, wherein saidmedicinal product is formulated for intravenous infusion, intramuscularinjection, or subcutaneous injection.
 38. The method according to claim32, wherein said medicinal product is formulated so that the activesubstance will pass into the ventricles of the patient's brain when itis administered to a patient.
 39. The method according to claim 32,wherein said medicinal product is formulated so that the activesubstance will pass into the cerebrospinal fluid of the patient when itis administered to a patient.
 40. A method for the treatment of anabnormal condition affecting the central nervous system, wherein saidabnormal condition is the consequence of axonal damage caused byconcussion, axonal damage caused by head trauma, axonal damage caused bysmall vessel disease in the CNS, damage to the spinal cord after diseaseand/or trauma comprising administering an effective amount of asubstance to a patient whereupon administration of said substance willlead to a decreased concentration of growth hormone or a functionallyequivalent analog thereof.
 41. The method according to claim 40, whereinsaid substance is a negatively regulating growth hormone bindingprotein, a functionally equivalent analogous thereof, an antibodyagainst growth hormone, a biologically active growth hormone receptorinhibitor, and/or an inhibitor of endogenous growth hormone release. 42.A method of propagating cells selected from the group consisting ofneuronal progenitor cells and neuronal stem cells by administration of acomposition comprising an amount of a growth hormone effective topropagate neuronal progenitor cells and neuronal stem cells in vitro.43. A method of inducing lineage determination or inducing ormaintaining the genesis of neurons, oligodendrocytes, astroglia cellsfrom progenitor cells or stem cells in, or derived from, the central orperipheral nervous system in a patient, wherein a pharmaceuticallyeffective amount of growth hormone or a functionally equivalent analoguethereof is administered to a patient in need thereof.
 44. A methodaccording to claim 43, for treatment of an abnormal condition affectingthe nervous system of a patient.
 45. A method according to claim 44,wherein said condition affects the oligodendroglia, astroglia, orneuronal cells.
 46. A method according to claim 44, wherein saidcondition affects the non-cholinergic neuronal cells, cholinergicneuronal cells, or glial cells.
 47. A method according to claim 44,wherein said condition is a CNS damage or deficit.
 48. A methodaccording to claim 47, wherein said condition is neural cell loss.
 49. Amethod according to claim 47, wherein said condition is memory loss. 50.A method according to claim 47, wherein said condition is caused by atleast one factor selected from the group consisting of multiplesclerosis, hypoxic injury, ischemic injury, traumatic injury,Parkinson's disease, and demyelinating disorder.
 51. A method accordingto claim 43, wherein said substance is administered by intravenousinfusion, intramuscular injection, or subcutaneous injection.
 52. Amethod according to claim 43, wherein brain cells are removed from thepatient after said administration, said brain cells then beingpropagated in vitro, followed by transplantation of the obtained cellsback into the brain of a patient in need thereof.
 53. A method accordingto claim 52, wherein an effective amount of growth hormone or afunctionally equivalent analogue thereof is administered to said braincells during in vitro propagation.
 54. A method of reducing the genesisof oligodendrocytes, neurons, astroglia cells from progenitor cells orstem cells in, or derived from, the central or peripheral nervous systemin a patient, wherein a pharmaceutically effective amount of a substancethat will lead to a decreased concentration of growth hormone or afunctionally equivalent analogue thereof is administered to a patient inneed thereof.
 55. A method according to claim 54, wherein said substanceis administered to the peripheral or central nervous system of saidpatient.
 56. A method according to claim 54, wherein said substance isselected from the group consisting of negatively regulating growthhormone binding proteins, functionally equivalent analogous thereof,antibodies against growth hormone, biologically active growth hormonereceptor inhibitors, and inhibitors of endogenous GH release.
 57. Amethod according to claim 54, for treatment of a central nervous systeminjury.
 58. A method according to claim 57, wherein said injury is theconsequence of a factor selected from the group consisting of axonaldamage caused by concussion, axonal damage caused by head trauma, axonaldamage caused by small vessel disease in the CNS, damage to the spinalcord after disease or trauma.
 59. A method of claim 42, wherein thecells are isolated from mammalian central nervous system.
 60. A methodof claim 42, wherein the mammalian central nervous system is a humancentral nervous system.